Impaired plasmacytoid dendritic cell maturation and differential chemotaxis in chronic hepatitis C virus: associations with antiviral treatment outcomes
Impaired plasmacytoid dendritic cell maturation and differential chemotaxis in chronic hepatitis C virus: associations with antiviral treatment outcomes
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DOI：
10.1136/gut.2008.168948
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发表时间：
2009-07-01
期刊：
影响因子：
24.5
通讯作者：
Rosen, H. R.
中科院分区：
文献类型：
--
作者：
Mengshol, J. A.;Golden-Mason, L.;Rosen, H. R.
背景：树突状细胞 (DC) 缺陷可能导致丙型肝炎病毒 (HCV) 感染慢性化，并通过 T 细胞刺激不良决定对 PEG-干扰素和利巴韦林治疗的反应。迄今为止的研究在 DC 成熟和功能方面产生了不一致的结果：没有大型研究检查治疗前后的 DC。目的：我们通过比较治疗反应者与无反应者来检查 DC 成熟和趋化性是否存在缺陷。方法：我们分析了来自 Virahep-C 研究的 64 名 HCV 基因型 1 感染患者在治疗前 2 周和治疗后 24 周的外周 DC。我们使用流式细胞术来计数浆细胞样 DC (pDC) 和髓样 DC (mDC)，并量化趋化因子受体和成熟标记物的表达。通过体外测定测量趋化性。结果：HCV 患者中 pDC 和 mDC 的治疗前频率显着低于对照组和成功治疗后标准化的 pDC。与正常对照相比，pDC 上的 CXCR3 和 CXCR4 水平在基线时较高，并随着治疗而降低。与正常患者相比，慢性 HCV 感染患者的 pDC 治疗前共刺激标志物 CD40 和成熟标志物 CD83 的水平较高，并且仅 SVR+ 组治疗后两种标志物的水平均显着下降。其他成熟标志物（CD86 和 CCR7）未升高，表明表型部分激活。 pDC 对 CXCL12 和 CXCL10 的基线趋化性预测抗病毒反应失败，并与组织学活动指数炎症评分相关。结论：慢性 HCV 中存在浆细胞样 DC 缺陷，成功的抗病毒治疗使许多表型和功能异常正常化。
Background: Dendritic cell (DC) defects may contribute to chronicity in hepatitis C virus (HCV) infection and determine response to PEG-interferon and ribavirin therapy via poor T cell stimulation. Studies to date have produced inconsistent results regarding DC maturation and function: no large study has examined DCs before and after therapy.Aims: We examined if DC defects in maturation and chemotaxis are present by comparing therapeutic responders to non-responders.Methods: We analysed peripheral DCs of 64 HCV genotype 1-infected patients from the Virahep-C study 2 weeks before and 24 weeks after therapy. We used flow cytometry to enumerate plasmacytoid DC (pDC) and myeloid DCs (mDC) and quantify expression of chemokine receptors and maturation markers. Chemotaxis was measured with an in vitro assay.Results: Pre-treatment frequencies of pDCs and mDCs were significantly lower in HCV patients than controls and successful therapy normalised pDCs. Levels of CXCR3 and CXCR4 on pDCs were higher at baseline compared to normal controls and decreased with therapy. Pre-therapy levels of co-stimulatory marker CD40 and the maturation marker CD83 were higher in pDCs of patients chronically infected with HCV compared to normal patients, and levels of both markers dropped significantly with therapy in the SVR+ group only. Other maturation markers (CD86 and CCR7) were not elevated suggesting a partially activated phenotype. Baseline chemotaxis of pDCs to CXCL12 and CXCL10 predicted failure of antiviral response and correlated with the histological activity index inflammation score.Conclusions: Plasmacytoid DC defects exist in chronic HCV and successful antiviral therapy normalises many phenotypic and functional abnormalities.